After menopause, when estrogens decrease, the incidence of obesity and cardiovascular disease increases dramatically. Obesity has been linked to hypertension; however, not every woman who undergoes menopause develops obesity and hypertension. Several studies have shown that human obesity can raise blood pressure (BP) by activating the renin-angiotensin system (RAS) and human obesity is associated with hyperleptinemia, which in animal models causes hypertension through activation of the sympathetic nervous system (SNS). Therefore, the goal of this proposal is to study the role of estrogen deficiency in promoting obesity and hypertension after menopause and specifically address the importance of hyperleptinemia, increased RAS and SNS activity in contributing to postmenopausal hypertension. Female rats that are ovariectomized when they are old combine the two most important characteristics of menopause, increased age and decreased estrogens and will be used to test the hypothesis that increases in body weight associated with lack of estrogens after menopause raises BP via leptin-induced SNS activation and activation of the RAS in the following aims: 1) To test the role of decreases in estrogens in promoting the development of post-menopausal obesity induced hypertension, by addressing the direct effects of decreases in estrogens in BP or through alterations in appetite and physical activity during aging. 2) To test whether decreases in estrogens after menopause activate the RAS, which in turn contributes to the development of post-menopausal hypertension (measuring RAS components, and BP after RAS blockade in presence or absence of estrogens). 3) To test whether decreases in estrogens contribute to SNS activation (studying the effects of SNS blockade and renal denervation on BP), via increases in leptin (addressing the cardiovascular effects of leptin depending on the estrogenic status), which contributes to postmenopausal hypertension. Women spend more than a third of their life in post-menopause, when the incidence of obesity and cardiovascular disease increases. Therefore, identifying the mechanisms involved in the development of obesity and hypertension after menopause may result in the development of new therapeutic approaches for a very important women's health issue. It will also obtain additional information about the controversial effects of hormone replacement therapy on blood pressure after menopause. [unreadable] [unreadable] [unreadable]